tbuckley/cabot-search huggingface dataset:
Abstract 5949: Modulate TAM infiltration at cancer-immune interface by targeting at monocyte migration
Authors: Wenxuan Du, Adrian Johnston, Praful Nair, Jingyi Zhu, Khin Sandar Win, Bryan Zhou, Jude Phillip, Pei-Hsun Wu, Denis Wirtz
Journal: Cancer Research (2023)

Abstract Extensive infiltration of tumor-associated macrophages (TAMs) into the solid tumor microenvironment (TME), where they promote angiogenesis, initiate metastasis, and tune immunosuppression, has long been proven to correlate with worse patient prognosis. Thus, much significance has been attached on either impeding TAM infiltration or reversing pro-tumoral TAMs back into phagocytic M1 phenotype. Nevertheless, while revealing underlying mechanisms of blocking TAM recruitment, widely adopted in vitro migration assays like Transwell, µ-slides fail to distinguish cell’s random migration from chemotaxis (biased migration) and introduce 3D extracellular matrix environment. Here we present data that monocytes, as major replenishment source of TAMs, massively boost their random migration via paracrine pathway to initiate early-stage infiltration using an advanced 3D multi-compartment organoid model. In addition, before re-educated into TAMs, monocytes in the TME are capable of inducing triple negative breast cancer cells’ hyper-proliferation by activating their MEK/ERK signaling pathway. This work provides evidence that TAM infiltration is driven by monocytes’ random/biased migration separately and identifies a potential combinational immunotherapy targeting at monocytes instead of TAMs. Citation Format: Wenxuan Du, Adrian Johnston, Praful Nair, Jingyi Zhu, Khin Sandar Win, Bryan Zhou, Jude Phillip, Pei-Hsun Wu, Denis Wirtz. Modulate TAM infiltration at cancer-immune interface by targeting at monocyte migration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5949.
Abstract 3916: role of her3 v104l mutation on tumor growth and her3 stabilization
Authors: Rosalin Mishra, Mary Kate Kilroy, Wasim Feroz, Hima Patel, Samar Alanazi, Joan T. Garrett
Journal: Cancer Research (2023)

Abstract We aimed to determine if naturally occurring HER3 mutations could drive oncogenic activity of HER2+ HCC1569 cells in which endogenous HER3 was knocked out using CRISPR-Cas9 technology. A series of HER3 mutations found in breast cancer patients (F94L, V104L, G284R, D297Y, T355I, and E928G) were introduced via lentiviral transduction and stable cell lines were generated in HER3 knock out (KO) HCC1569 cells and were maintained in 0.5 mg/mL puromycin. Our data indicated that cells stably transduced with HER3V104L mutation had significantly higher cell growth with higher p-HER3 expression versus wild-type (wt) and empty-vector (EV) HER3. We found that HCC1569HER3KO cells with WT and V104L were sensitive to increasing concentration of neratinib (0.1-0.5 µM) as indicated by crystal violet assay. Next we examined if V104L mutation rendered resistance to another FDA- approved irreversible HER2 tyrosine kinase inhibitor, tucatinib. Our results showed that V104L cells were sensitive to higher concentration of tucatinib compared to neratinib. In other experiments, we used COS7 cells to examine the signaling pathways of HER3V104L mutation. Our western blot data demonstrated that transient transfection of COS7 cells with HER3V104L mutant significantly upregulated p-HER3 and p-HER2 expression versus WT HER3 in a NRG- dependent manner. In addition, we found that the V104L mutation stabilizes HER3 protein expression independent of ligand stimulation. Our western blot data showed that V104L induced HER3 stabilization is independent on HER3 binding partners HER1, HER2 and HER4. Our cycloheximide chase data indicated that V104L mutation stabilizes HER3 expression in COS7 cells as well as low HER3 expressing colon cancer cell line, SNUC5. Our western blot data indicates that V104L mutation activates ERK signaling in NRG dependent manner over AKT pathway in COS7 cells. In addition, we are using various PDXs with different HER3 mutations (V104M and E928D) to determine the role of these driver HER3 mutations in cancer and how this can be targeted in the clinic using HER targeted therapy. Citation Format: Rosalin Mishra, Mary Kate Kilroy, Wasim Feroz, Hima Patel, Samar Alanazi, Joan T. Garrett. role of her3 v104l mutation on tumor growth and her3 stabilization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3916.
Abstract 2397: An advanced approach technique for tracking point between immune check point inhibitor and cancer cell mechanism in immune response motility by infiltration a breast cancer cell
Authors: Hyunseok Kim, Soyeon Ahn, Hyungjin Kwon, Hsuan-Ju Chen, Inwon Park, Pilhan Kim, Akyildiz Kubra
Journal: Cancer Research (2023)

Abstract In Breast Cancer, Tumor-infiltrating lymphocyte (TIL) motility has been reported that it is reflecting tumor microenvironment response by adoptive cell therapy (ACT). ACT is well-known to be best applied for suppressing cancer cell growth with immune response and it also was well-known the immunotherapy. However, ACT response tracking by general analysis method included immunohistochemistry and flow cytometry was provided limited information for cancer therapy in recent years. Therefore, by assessing relationship immunotherapy marker, PD-L1, known as immune check point inhibitor and TIL using intravital microscopy in breast cancer model, we also imaged whether TIL response was related to immunotherapy following dependent on time point in a various breast cancer cell implanted mouse model such as 4T1 (mouse breast cancer cell), MDA-MB-231 (human triple negative breast cancer cell) and MCF7 (human breast cancer cell). These images result in PD-L1 expression was decreased in cancer cell implanted until 10days, whereas TIL expression increased in a various breast cancer cell when it is measuring displacement length, track mean velocity and confinement ratio called tumor microenvironment. These results indicated that we can imaged immune response related to TIL response in breast cancer cell line by intravital microscopy instead of general microscopy. It means that intravital microscope was an advanced approach technique to understand cancer mechanism accompanied by the immune response and established the method of high-resolution intravital cellular visualization compared to a general histopathological method for evaluating immune response in cancer tissue Citation Format: Hyunseok Kim, Soyeon Ahn, Hyungjin Kwon, Hsuan-Ju Chen, Inwon Park, Pilhan Kim, Akyildiz Kubra. An advanced approach technique for tracking point between immune check point inhibitor and cancer cell mechanism in immune response motility by infiltration a breast cancer cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2397.
Abstract 3988: The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance
Authors: Mary K. Kilroy, Rosalin Mishra, Anastasia Stupecki, Wasim Feroz, Samar Alanazi, Joan T. Garrett
Journal: Cancer Research (2023)

Abstract Colorectal cancer is a disease of the colon and rectum that will claim about 52,580 American lives in2022. The most common treatment of colorectal cancer is surgery plus chemotherapy, although thereare some FDA approved targeted therapies such as regorafenib (targeting VEGF) or cetuximab (targetingEGFR). EGFR, along with HER2, HER3, and HER4 are members of the HER family of receptor tyrosinekinases that upon homo- or heterodimerization activate downstream signaling, growth, and survivalpathways. In recent years, more attention has been paid to HER2 and HER3’s roles in colorectal cancers,as they may cause resistance to targeted therapies. OWe are investigating naturally occurring mutantHER3’s role in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation. We arecurrently investigating how HER3 mutations may affect sensitivity to current therapies through HERfamily receptor dimerization and be involved in tumor metastasis. We are assessing the degree to whichmutant and wild-type HER3 have the ability to dimerize with EGFR, HER2, MET, and IGF1R the resultingeffects in colon cancer, as these receptor tyrosine kinases are HER3 binding partners. As HER3 bindingpartners are diverse, it may be that the pathway HER3 and its binding partner activate may influencetreatment strategy. It has been noted that mutant HER2 and HER3 could confer sensitivity to HER familyinhibitors, i.e. afatinib, in bladder cancer, and we have seen a difference in IC50 values of afatinibbetween cell lines containing wild-type or mutant HER3. If mutant HER3 is involved in therapeuticresistance or sensitivity and tumor progression, our findings may present a new biomarker for targetedtreatments in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary K. Kilroy, Rosalin Mishra, Anastasia Stupecki, Wasim Feroz, Samar Alanazi, Joan T. Garrett. The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3988.
Abstract 6598: The development of a tumor-agnostic liquid biopsy assay for minimal residual disease detection and monitoring in cancers
Authors: Giancarlo Bonora, Hang Dong, Chao Dai, Binggang Xiang, Billie Gould, Tiantian Zhen, Wei Mo, Xiaohong Wang, Kemin Zhou, Shidong Jia, Shujun Luo, Pan Du
Journal: Cancer Research (2023)

Abstract Purpose Non-invasive liquid biopsy (LBx) based assays hold great promise for early cancer diagnosis and disease progression monitoring. Personalized baseline tissue-informed minimal residual disease (MRD) monitoring exhibits a particularly high detection sensitivity in many studies, however, baseline samples (especially tissue biopsies) are often difficult to acquire in a clinical setting, and the personalized panel design and tracking creates operation complexities. Methods We developed PredicineALERTTM, a baseline-agnostic MRD LBx assay that measures methylation and mutational variants associated with cancers. At its core lies the PredicineEPICTM DNA methylation assay with the advantage of low DNA damage and low input amount. Tumor burden is assessed by detecting abnormally methylated DNA fragments with high sensitivity using the Predicine DeepSea bioinformatics analysis pipeline. PredicineALERTTM provides integrated methylation and mutational profiling, as well as copy number variation (CNV) profiling. Results The PredicineALERTTM assay was tested using longitudinal LBx samples (blood, urine, CSF) from patients with mCRPC, CRC, NSCLC, breast, liver, kidney, prostate, and bladder cancers. The PredicineALERTTM assay demonstrates highly-sensitive MRD detection and quatification capability (LOD &amp;lt; 0.01%) using 2.5 - 15ng input cfDNA. It has the ability to identify unique cancer biomarker signatures, and robustly detect MRD ctDNA dynamics during treatment. By leveraging genome-wide fragment-level DNA methylation, PredicineALERTTM measures molecular response and MRD in targeted therapy, immunotherapy and chemotherapy. A strong concordance was observed in the pattern of tumor burden as ascertained by CNV and methylation analyses, respectively. Conclusion We developed PredicinceALERTTM, a baseline agnostic, multidimensional MRD LBx assay without the need for baseline samples and personalized panel design. It integrates DNA methylation, mutation, and copy number changes for detecting MRD from genome-scale data without relying on target selection before library generation. Citation Format: Giancarlo Bonora, Hang Dong, Chao Dai, Binggang Xiang, Billie Gould, Tiantian Zhen, Wei Mo, Xiaohong Wang, Kemin Zhou, Shidong Jia, Shujun Luo, Pan Du. The development of a tumor-agnostic liquid biopsy assay for minimal residual disease detection and monitoring in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6598.
Abstract 2567: Exploring novel roles of the GPCR Smoothened in AKT signaling and drug resistance
Authors: Samantha Manuel, Nitin Agarwal, Daniel Bilbao, Francisco Vega, Ralf Landgraf
Journal: Cancer Research (2023)

Abstract The Smoothened receptor (SMO) belongs to the frizzled-class-G-protein coupled receptor and its activity can be classified in the canonical and the non-canonical pathway. The canonical pathway concludes in the transcriptional activation of the Hedgehog target genes through the GLI family of transcription factors whereas the non-canonical pathway leads to the recruitment and activation of trimeric G proteins. Recently, we have reported two novel roles of SMO with relevance to cell survival and drug resistance in DLBCL. In the first, SMO promotes a shift in the ubiquitination pattern for TNF receptor-associated factor 6 (TRAF6) from degradation inducing K48-ubiquitin branching towards K63-ubiquitination. TRAF6 is a K63-Ub E3 ubiquitin ligase for AKT and K63-ubiquitination of AKT increases membrane recruitment, activation and stability. Evidently, SMO promotes the formation of a scaffold-like protein complex including the de-ubiquitinating enzyme Ubiquitin specific peptidase 8 (USP8) and TRAF6. In its second novel role, SMO influences the vesicular sorting of IGF1R and other receptor tyrosine kinases. Loss of SMO leads to increased IGF1R lysosomal degradation and reduced IGF1R recycling, while overexpression increases IGF1R levels and AKT signaling. These observations indicate SMO receptor biology outside of the established canonical and non-canonical pathway functions. We have set out to use BioID to investigate the SMO interactome that contributes to these novel functionalities using a fusion protein of SMO and the reengineered E. coli biotinyl transferase BirA (Turbo) as bait. Preliminary BioID using SMO-Turbo returned a list of candidates which will require further data filtering approaches, but thus far shows a marked enrichment for proteins involved in vesicular trafficking. Citation Format: Samantha Manuel, Nitin Agarwal, Daniel Bilbao, Francisco Vega, Ralf Landgraf. Exploring novel roles of the GPCR Smoothened in AKT signaling and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2567.
Abstract 5168: <i>In vitro</i> suppressive Treg bioassays for screening of candidate therapeutics
Authors: Martijn Vlaming, Alanah Pieters, Jezabel Lefevere, Sofie Pattyn
Journal: Cancer Research (2023)

Abstract The increasing interest in the tumor microenvironment leads to a focus on new bioassays to represent all the players of the cancer immune response. Some of these players like regulatory T cells play an important role by downregulating the anti-tumor response. Their regulation mechanisms constitute an important target for new therapeutics. In order to study these mechanisms in a human model, suppressive Treg bioassays mimicking the suppressive action of these cells were developed and optimized. In vitro suppressive assays come with many technical challenges, therefore protocols for the purification and in vitro culture of regulatory T cells were optimized and fine-tuned to result in an optimal assay window e and allow screening of multiple candidates. Donor-to-donor variation is controlled by pre-evaluation of multiple donors and standardized methods are used for isolation and in vitro culture of responding and suppressive cells. Access to a large and broad panel of healthy donors is required for the evaluation of therapeutic agents targeting the regulatory T cell pathway. Citation Format: Martijn Vlaming, Alanah Pieters, Jezabel Lefevere, Sofie Pattyn. In vitro suppressive Treg bioassays for screening of candidate therapeutics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5168.
Abstract 4347: A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine
Authors: Seth Salpeter, Vered Bar, Guy Neev, Adi Zundelevich, Gil Rosen, Sandra Hanks, Naoise Costelloe, Jonathan Krell, Ravid Straussman
Journal: Cancer Research (2023)

Abstract Precision cancer therapy has the potential to revolutionize treatment outcome. While genomic analysis has become central to cancer personalized medicine, recent studies have not shown that it drastically improves the patient’s survival as compared to standard drug selection. Additionally, genomic mutations may suggest several treatment protocols without elucidating which approach will yield the best clinical response. To advance cancer precision guidance, we have developed cResponse, a combined genomic-functional drug sensitivity platform to determine individualized patient treatment regimens. Fresh patient cancer samples are taken by biopsy or resection and sectioned into 250uM slices which when cultured in cResponse platform demonstrate similar architecture and tissue proliferation to those found in vivo. An initial clinical study showed that cResponse can preserve human cancer tissue in 3D culture together with its microenvironment, including endothelial and immune cells, at a high viability (&amp;gt;90%) with continued cell division for more than 7 days. On a cohort of 34 patients treated with neoadjuvant therapy or systemic therapy for metastatic disease, the assay was able to predict patient response to drug treatment with a sensitivity of 96% and a specificity of 77.7%. To further validate the capacity of the cResponse platform to predict patient response to cancer therapy, a follow up pivotal clinical study was established at 7 major cancer centers located in the UK with the goal of recruiting a total of 170 patients to provide a large statistical validation of the previous results. Here we report on the outcome of the first 50 patients recruited to the pivotal trial and describe the predictive results correlated to patient response. Citation Format: Seth Salpeter, Vered Bar, Guy Neev, Adi Zundelevich, Gil Rosen, Sandra Hanks, Naoise Costelloe, Jonathan Krell, Ravid Straussman. A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4347.
Abstract 4837: Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer
Authors: Sumati Hasani, Lyndsay E. Young, Moumita Banerjee, Dylan Rivas, Jinhwan Kim, Ramon Sun, Matthew Gentry, Xiaopeng Xiong, Tianyan Gao
Journal: Cancer Research (2023)

Abstract Metabolic reprogramming has been increasingly recognized as one of the major mechanisms that fuels tumorigenesis and disease progression. Our previous studies have shown that in response to fatty acid uptake, colon cancer cells activate mitochondrial fission to support fatty acid oxidation and downstream Wnt signaling. Given the potential benefit of inhibiting mitochondrial fission, Dynamin-Related Protein 1 (Drp1), a pro-fission factor, has become an attractive target for developing anticancer agents. Here we investigated the role of Drp1 in promoting metabolic adaptation in colon cancer. We found that knockdown of Drp1 decreased mitochondrial respiration which resulted in increased glucose uptake and lactate production. In addition, downregulation of Drp1 increased AMP-activated protein kinase (AMPK) activity which coincided with glycogen accumulation. Consistently, results from GC/MS analysis of cellular metabolites revealed that the levels of glucose-6-phosphate, a precursor for glycogenesis, were significantly elevated in Drp1 knockdown cells whereas pyruvate and other TCA cycle metabolites remained unchanged. Mechanistically, AMPK transcriptionally activates the expression of glycogen synthase 1 (GYS1) and hexokinase 2 (HK2) genes and silencing GYS1 abolished the glycogen accumulation phenotype in Drp1 knockdown cells. Using APC-derived 3D organoids, we demonstrated that the glycogen levels were elevated in Apcf/f Drp1f/f tumor organoids upon deletion of Drp1. Similarly, increased GYS1 expression and glycogen levels were detected in xenograft tumors derived from Drp1 knockdown colon cancer cells compared to control. Functionally, increased glycogen storage allowed Drp1 knockdown cells to survive glucose starvation conditions suggesting an enhanced survival capacity compared to control cells. Taken together, our findings indicate that Drp1 inhibition by itself is unlikely to be sufficient to eradicate cancer cells as adaptive metabolic mechanisms are activated to promote cell survival. However, combining Drp1 inhibition may enhance the efficacy of chemotherapeutic agents for colon cancer treatment. Citation Format: Sumati Hasani, Lyndsay E. Young, Moumita Banerjee, Dylan Rivas, Jinhwan Kim, Ramon Sun, Matthew Gentry, Xiaopeng Xiong, Tianyan Gao. Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4837.